Pneumonia and influenza, taken together, are a leading cause of hospitalization and death in the United States. Although it has been appreciated for more than two centuries that influenza predisposes the host to secondary bacterial infections, the incidence and etiology of influenza-associated pneumonia has never been comprehensively studied. Several epidemiologic trends are fueling a desire to gain better insight into interactions between viruses and bacteria in the pathogenesis of pneumonia. In studies employing comprehensive diagnostic methods, the incidence of co-infections in CAP appears to be at least 40%. For these reasons, the time is right to undertake prospective study of the role of co-infections in pneumonia in children using comprehensive and sensitive diagnostic assays. We propose to conduct a clinical study of the incidence and etiology of pneumonia in hospitalized children at Le Bonheur Children's Medical Center and St. Jude Children's Research Hospital in Memphis, Tennessee. We will use this opportunity to answer some interesting and important scientific questions about co-infections in this population. The underlying hypothesis for our Proposed Studies is that co-infections result in poorer outcomes than single infections. We will test this hypothesis by prospectively collecting sociodemographic, microbiological, clinical, and genomics data to determine associations with clinical outcomes. PUBLIC HEALTH RELEVANCE: Pneumonia and influenza are the 5th leading cause of death for children in the United States and the leading cause of death in the developing world outside the neonatal period. It is likely that co-infections contribute significantly to these statistics, but only sparse relevant data are available on incidence and etiology of CAP in children, and no data are available comparing single infections to co-infections. Since treatment and prevention of co-infections are likely to be different and more difficult for co-infections than single infections, it is important to understand the incidence and etiology of CAP, potential differences in outcomes for co-infections compared to single infections, and the strains and gene expression profiles that contribute to poorer outcomes. This is particularly important and topical with the increased incidence of methicillin-resistant S. aureus (MRSA) cases found to be complicating influenza following the emergence of the USA400 and USA300 strains.